ABSTRACT ! Allergic diseases (asthma, rhinitis, sinusitis, food allergy, etc), thought to arise because of maladaptive innate sensing of harmless environmental protein, and development of aberrant type 2 responses. However, why only certain individuals mount inappropriate type-2 immune responses to otherwise innocuous proteins remains an unanswered question. Evidence suggests that pattern recognition receptors (PRR) are a central mechanism through which the host senses its environment and have been shown to control several aspects of allergic diseases. We have identified the C-type lectin, dectin- 1 (CLEC7A), a PRR, as a protective receptor in manifestations of experimental allergic asthma and food allergy. Unexpectedly, we find that is not through binding b-glucans, its prototypical ligand, but through a completely novel interaction with invertebrate tropomyosin, a conserved protein found in all arthropods (mites, crustaceans, cockroach, etc). Surprisingly, the ligation of dectin-1 by house dust mite tropomyosin (Der p 10) confers protection against aberrant type 2 responses. Consistent with that, we find that dectin-1 also confers protection against food anaphylaxis in a shrimp (crustacean) allergy model. We find that dectin-1 sensing of Der p 10 confers protection through the regulation of epithelial IL-33 production, and the downstream recruitment of IL-13-producing innate lymphoid 2 (ILC2) cells. Validation of the role of dysregulated dectin-1 activity in conferring susceptibility to allergy is demonstrated by impaired dectin-1 expression in respiratory epithelial cells from asthmatic and chronic rhinosinusitic patients. We find that aberrant epithelial IL-33, through activation of STAT3, represses a unique region of the CLEC7A locus in non-hematopoietic cells (ClEc7a Nonhematopoietic-SpEcific Region- CENSER). This loop maintains repressed epithelial dectin-1 and perpetuates allergenicity to arthropods. Overall, these studies have identified a previously unrecognized innate immune recognition pathway which plays a critical role in dampening type-2 inflammation to arthropods, and that susceptibility to the allergic diathesis may be due to dysregulation of this critical regulatory pathway. We propose three specific aims to understand the initiation and regulation of arthropod allergies through the regulation of this pathway. Specific Aim 1 will further our understanding of how dectin-1 represses IL-33. Specific Aim 2 will determine the epigenetic regulation of the CLEC7A locus. Specific Aim 3 will demonstrate that dectin-1 repression in allergic individuals is driven by an aberrant IL- 33/STAT3 axis. Collectively, the studies proposed will expand our understanding of how type innate 2 responses develop, and enable us to identify novel therapeutic targets in individuals with dysregulated type 2 responses that are underserved by current therapies.